The purpose of this proposed research is to investigate the sequential cellular events and factors involved in gamma-glutamyltranspeptidase negative (GGT-) hepatocacinogenesis induced in the rat by various hypolipidemic peroxisome proliferators. The specific aims of this proposal are: 1) to investigate the sequential development of altered areas, neoplastic nodules (NN) and hepatocellular carcinomas (HCC) induced by selected hypolipidemic agents with special emphasis on GGT acitivity; 2) to determine whether the GGT negative phenotype of these various lesions is stable or reversible, i.e. whether GGT can be induced by various manipulations; 3) to determine whether GGT negativity is related to the absence, or to the inactivity of the enzyme; 4) to examine whether Wy-14,643 has any effect on GGT activity in altered areas and NN induced by genotoxic carcinogens; and 5) to evaluate altered areas, NN and HCC for other enzyme alterations such as glucose-6 phosphatase (G6Pase), adenosine triphosphatase (ATPase) and epoxide hydratase (EH), as well as their ability to exclude parenterally administered iron. Comparison of sequential events of GGT negative and GGT positive hepatocarcinogenesis may provide useful information concerning the hepatocarcinogenesis by mutogenic as compared to non-mutogenic carcinogens and factors involved in the expression versus non-expression of GGT.